Background
The new Variations Regulation (EC/1234/2008) (external link) was implemented on 1 January 2010. This immediately applied to variations to marketing authorisations covered by European procedures. However, the MHRA has also applied it to purely national variation applications from then.
As a result, and in continuation of previous practice, the MHRA has implemented an audit procedure for the new Type IA notifications. This involves auditing a statistically significant number of Type IA applications that have been processed each month. The actual number audited depends on the number processed.
This is to ensure that companies are submitting the new Type IA notifications correctly and also to identify any trends or areas of concern that companies may need to address. It is also to ensure that the MHRA is applying a consistent approach in the processing of these applications and enables us to amend our internal procedures accordingly.
Quality auditing of new Type IA notifications
The Audit Review Panel lead assessor will prepare a list of applications Type IA immediate notifications (IN) and Type IA annual notifications (ANN). The lead assessor will document findings of the quality audit (QA) and implement the decisions of the Audit Review Panel.
The following areas of deficiencies will be recorded:
- compliance/non-compliance with conditions of the notification
- documentation complete/incomplete
- grade of audit decision/result (ie satisfactory, minor, critical)
- recommended action
-
- internal based on data entry and quality of decision
- external based on validity and quality of submission
- other factors that may affect the audit outcome such as:
-
- inappropriate grouping submissions
- implementation dates
- label/leaflet
- payment of correct fee
- administrative procedures/ incorrect declarations
- inspection issues.
Depending on the findings of the QA Review, internal and/or external action may be required.
The results of the audit will be graded at three levels:
- Satisfactory – no further action required
- Minor – may require minor amendment
- Critical – further internal/external action required.
(NB: please refer to General Section Q.15 of the Q&A variations web page for classification of these deficiencies)
If the notification is considered to have a critical deficiency the applicant will be notified by a post-audit review letter. This identifies the nature of the deficiency and the remedial actions required.
Variation notifications June - 2010
Discussion of results
A representative sample of TIA notifications was audited during June 2010. The total number received and processed was 775. These include both Type IA (IN) and TIA (ANN) notifications.
The results are summarised in Table 1 and are divided into those obtained pre-and post-audit.
Key observations:
1) During the one-month period, out of the 775 Type IA notifications processed, 488 notifications were found to be valid and 283 notifications were invalidated prior to audit.
2) Following the audit, a further six Type IA variations were found to require further action.
3) The withdrawals (14) were made at either the classifier’s or company’s request owing to errors occurring during submission.
Outcomes
A crucial outcome of the audit procedure is the feedback of decisions made both internally and externally. These also result in follow up actions to resolve technical issues and clarification/correction of submissions and/or letters to industry.
In the light of the recent audit, a list of deficiencies has been identified and summarised in Table 2.
Key observations (audit review of deficiencies):
1) 36% of Type 1A notifications had been identified as invalid pre-audit with a further 2% (post-audit) with deficiencies potentially leading to invalidation some requiring remedial action.
2) Approximately 2% of Type IA notifications had been withdrawn owing to errors occurring during submission.
3) Examples of deficiencies are varied, but include: missing guideline, checklists, declarations, Summaries of Product Characteristics (SPC), patient information leaflet (PIL), wrong change codes, full or partial refusal of groupings, and implementation dates.
Summary
The audit of the new Type 1A notification procedure has generated a preliminary data set for the month of June 2010.
From an operational perspective, the implementation of the new variation procedure has been successful, with the introduction of clear regulatory guidelines and modifications to Sentinel.
During the one month period, out of the 775 Type IA notifications processed, 488 notifications were found to be valid and 283 notifications were invalidated prior to audit.
Following the audit, a further six Type IA variations were found to require further action. Most withdrawals (approximately 2%) were made at either the classifier’s or company’s request owing to errors occurring during submission.
The audit process has so far identified a close correlation with the pre-audited data. However, in order to maintain satisfactory quality assurance, the audit procedure will continue to regularly review cross-samples of notifications received. This will establish a comprehensive database of observations and trends.
An analysis of pre-audited data for Type IA notifications has recently been collated and documented in a related report titled ‘Type IA Variations – Experience to Date’ which is currently posted on the variations section of the MHRA website.
For further information please contact Dr Don Burford on 020 3080 6431 or Dr Keith Pugh on 020 3080 6427. Enquiries may also be sent to our email address: variationqueries@mhra.gsi.gov.uk
Table 1: Sample of TIA notifications audited during June 2010
Period covered 01/06/2010- 30/06/2010 – Non BROMI/BROMI - Pre audit
| Month | Pre audit | Post audit | ||||||
|---|---|---|---|---|---|---|---|---|
| Granted | Invalid | Withdrawn | Total | Granted | Invalid | Withdrawn | Total | |
| June | 478 | 283 | 14 | 775 | 472 | 289 | 14 | 775 |
Table 2: List of observed deficiencies
|
Category number/change
|
Associated critical deficiencies | Associated common deficiencies |
|---|---|---|
|
A1 |
No checklist was provided. |
Inconsistency in the submission of documentation from a ‘relevant official body’ has been observed for category A1 and A4. |
|
A4, B.III.1 |
Implementation dates provided either in the future or before the new procedure commenced |
Incorrect submissions of CoS have been observed in support of changes to the name of the AIM. In some cases (eg a CoS which is out of date), this can result in an invalid notification. |
|
A5 |
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The wording to this change has caused some confusion as it refers only to a change in the licence holder’s address details. It does not refer to the actual site of manufacture, which would be change code B.II.b.1 (Type IB). |
|
B.II.b.1 |
Batch release from non-EU site included. |
---------------------- |
|
B.II.b.2 |
QP statement was not sufficient. It needs an all inclusive statement or separate statements from each FP Manufacturer. The QP statement does not specifically mention each of the active manufacturers |
---------------------- |
|
B.I.b.1 |
Multiple changes including particle size specification requiring assessment – should be Type II. |
Changes were observed which included relaxation of specifications. |
|
B.I.b.2 |
Change in solvents used in dissolution for optical rotation |
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|
|
B.III.1 |
Condition 4 marked N/A but CoS did not have a life to retest. Additional test included which is not part of EP Konograph – should be Type II. |
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|
|
B.II.c.3 |
TSE risk classification included additional complex changes – should be Type II. |
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|
|
B.III.2 |
Lack of clarity about changes being introduced – not exclusively to comply with Pharmacopoeia. |
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|
B.II.e.6 |
Wrong change code (should have been B.II.e.1). Primary packaging of sterile product (but excluded by conditions) – should be Type II. |
---------------------- |
|
B.II.b.4 |
No module 3 update submitted or details of validation batches. |
Insufficient batch data/validation protocol has been observed for a number of applications. |
|
B.II.d.2 |
Introduction of non-routine tests and relaxation of specifications – should be Type II. |
|
